ABSTRACT. We propose a Cooperative Study Group for the Autoimmune Disease Prevention initiative that will ?contribute knowledge critical to achieving the goal of designing and administering practical interventions to prevent one or more autoimmune diseases? (quotes are from RFA-AI-16-003). Our proposal is to define ?the role of genetic susceptibility and environmental influences in autoimmune disease?, to ?determine the mechanisms by which defined genetic risk alleles influence susceptibility to autoimmune disease?, and to facilitate the ?identification and elucidation of cellular and immune pathways that may provide targets for preventive interventions?. Preliminary data show sets of ~25 transcription factors and co-factors (TFs) that immunoprecipitate DNA sequences (ChIP-seq) at disease risk loci producing powerful associations (2.7?Relative Risk?40, 1.5E- 06?pc?4.6E-53) for each of 7 autoimmune diseases: multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), celiac disease (CelD), and systemic lupus erythematosus (SLE). These TFs prominently include one that is encoded by a virus, Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2), and nearly half of the associated TFs are known to be components of EBV associated super-enhancers. While the new results are compelling; the underlying data are currently incomplete and generally inadequate for technical and study design issues; nevertheless, we have identified several convincing examples of allele-dependent differences in TF binding to plausible causal variants from disease risk loci (e.g., at IL-10, CD37, and TMBIM1). These illustrate the nomination of specific molecular interactions for possible contributions to the consequent autoimmune disease; in addition, they provide powerful guidance for the data that should be developed in order to understand the interaction of environment (here EBNA2) with risk loci to produce autoimmune disease mechanisms. We propose 4 aims: We will test the association of nucleic acid binding by regulatory molecules (TFs, microRNAs, long non-coding RNAs, and RNA binding proteins) with autoimmune disease loci (Aim 1); we will generate experimental regulatory molecule binding data to reveal possible disease generating mechanisms (Aim 2); we will test specific hypotheses of gene regulation ex vivo and localize gene regulatory effects to individual variants with chromatin edited cell lines (Aim 3); and we will extend our new approach to our Autoimmune Prevention Study Group colleagues and their projects, as ?alpha testers? of our informatics and experimental approaches, in order to advance our basic understanding of autoimmunity as rapidly as possible (Aim 4). Overall, this project will provide pathophysiological mechanisms for autoimmune diseases, will couple the causal genes to environment for at least the example of EBV, will demonstrate how a much larger data resource could provide transforming insights into many diseases, and will generate ex vivo models that will provide reagents and data to facilitate the subsequent evaluation of therapies and preventive strategies.